Brief Report

Autoimmune thrombocytopenia in non-Hodgkins

lymphomas
Alexander W. Hauswirth,1 Cathrin Skrabs,1 Christian Schtzinger,1 Markus Raderer,2
Andreas Chott,3 Peter Valent,1 Klaus Lechner,1 and Ulrich Jger1
1
Department of Medicine I, Division of Hematology and Hemostaseology and 2Oncology, 3Department of Pathology,
Medical University of Vienna, Vienna, Austria

ABSTRACT
Autoimmune thrombocytopenia is a common immune-hematologic complication in non-Hodgkins lymphomas and may complicate the
treatment. We analyzed an original series from our institute as well as published cases of non-Hodgkins lymphomas (excluding chron-
ic lymphocytic leukemia) associated with autoimmune thrombocytopenia with regard to demographic factors, prevalence in non-
Hodgkins lymphoma subtypes and treatment outcome. The male/female ratio is 1.75. Half of the cases occurred prior to diagnosis of
lymphoma. Chemotherapy is the best treatment in many non-Hodgkins lymphomas patients with autoimmune thrombocytopenia com-
pared with standard treatment of autoimmune thrombocytopenia. Splenectomy is effective in splenic marginal zone lymphoma.
Autoimmune thrombocytopenia in patients with non-Hodgkins lymphomas is potentially life-threatening and difficult to treat.
Key words: autoimmune thrombocytopenias, non-Hodgkins lymphoma.
Citation: Hauswirth AW, Skrabs C, Schtzinger C, Raderer M, Chott A, Valent P, Lechner K, and Jger U. Autoimmune thrombocytopenia
in non-Hodgkins lymphomas. Haematologica 2008 Mar; 93(3):447-450. doi: 10.3324/haematol.11934
2008 Ferrata Storti Foundation. This is an open-access paper.

Introduction patients with lymphoma) from our institute. The case

Autoimmune phenomena are associated with non-
Hodgkins lymphoma (NHL). They may precede the clinical
presentation of NHL, occur concurrently or later, either spon-
taneously or following treatment.1-3 Among these phenome-
na, hematologic autoimmune diseases are a special subgroup
and include autoimmune hemolytic anemia (AIHA),4 autoim-
mune thrombocytopenia (ITP), Evanss syndrome, antibodies
to clotting factors,5 lupus anticoagulants6 and antibodies to
C1 esterase inhibitor.7 Less is known about the occurrence,
prognosis and treatment of ITP in NHL. The frequency of ITP
in chronic lymphocytic leukemia (CLL) and NHL has been
determined in several studies.8-15
We analyzed data of individual non-CLL NHL patients
with ITP from published case reports and original series of
our institute with regard to the temporal relationship
between ITP and lymphoma, the frequency in NHL sub-
types, laboratory data and treatment outcome.
Design and Methods
reports were retrieved using PubMed and Medline (1962-
2006) and from the reference lists of papers published in the
field. The histological diagnosis of the lymphomas was
made according to NHL classification at the time of publi-
cation. We converted the lymphoma diagnosis of the
authors to the WHO classification.16 Treatment outcome
was taken to be that confirmed by the authors: complete
remission=CR; partial remission=PR; no remission or
refractory=NR. The term transient complete remission=tCR
was used in cases in which there was a relapse after initial
successful treatment. Two authors independently analyzed
data. Statistical methods were not applied due to the small
number of cases.
Results
Overall prevalence of ITP in NHL
The prevalence of ITP in NHL (without CLL) in four large
studies (1,850 patients) was 0.76% (range 0-1.8%), the preva-
lence of Evanss syndrome 0.16% (8.12-14.17).

Data were taken from case reports published in the liter- Characteristics of individual patients with ITP in NHL
ature (n=32) with minimal diagnostic information on the ITP in small lymphocytic lymphoma (SLL)
underlying NHL (excluding B-CLL) and ITP as well as from One case of ITP-SLL has been described.18 This patient had
an original series (one case of an associated ITP in 292 ITP 12 months prior to a localized lymphoma of the liver

Manuscript received July 4, 2007. Manuscript accepted November 27, 2007.

Correspondence: Alexander Hauswirth, Department of Medicine I, Division of Haematology and Haemostaseology, Medical University of Vienna, Vienna, A
1090 Whringergrtel 18- 20, Austria. E-mail: alexander.hauswirth@meduniwien.ac.at

haematologica | 2008; 93(3) | 447 |

A.H. Hauswirth et al.
(stage IIE). The ITP responded only transiently to
steroids and splenectomy (SE), but a sustained com-
plete remission of ITP and SLL was achieved after
chemotherapy.
ITP in marginal zone lymphoma (MZL)
Seven MZL-patients associated with ITP have been
reported, including four patients with MALT lym-
phoma,19-22 two with splenic lymphoma with villous
lymphocytes (SLVL)23 and one with a nodular MZL.24
The male to female ratio was 0.4. In three cases the ITP
was diagnosed 1-10 years before diagnosis of lym-
phoma, in the other cases at the diagnosis of lym-
phoma. The MALT lymphomas were gastric lym-
phomas in three cases19, 21, 22 and a lung MALToma in one
case20 (stage IE to IIE). All patients in whom the lym-
phoma was removed surgically ( subsequent chemo-
therapy)19,21 or who received chemotherapy alone22
achieved a CR of ITP. By contrast, most of these
patients did not respond to steroids.19,22,24 The two
patients with SLVL achieved a CR of ITP after SE,
which was sustained in one and transient in the other.23
ITP in hairy cell leukemia (HCL)
Two patients with HCL had an ITP. In one case, ITP
was presented several months prior to diagnosis of
NHL.25 In another case, ITP developed after the diagno-
sis of lymphoma. This patient had received prior treat-
ment with pentostatin.26 Both patients were refractory
to steroids. One had a sustained CR (22 weeks+) after
rituximab26 and one after splenectomy.25
ITP in lymphoplasmacytic lymphoma, Waldenstrm disease
Three cases of associated ITP were reported,27-29 all
were male. ITP preceded the lymphoma in one29 and
was concurrent in the other two. In two cases, an IgM
antibody to platelets could be demonstrated, but the
specificity could not be defined. None of the patients
achieved a complete remission with conventional ITP-
treatments (steroids, HD-IgG, splenectomy).
ITP in other low-grade lymphomas
An association of ITP and mantle cell lymphoma was
reported in one case.30 This patient had a partial remis-
sion after rituximab as first line therapy. In an original
series of 171 cases with mantle cell lymphoma in our
institute we found no case of an associated ITP. We
have observed one female with an association of ITP
and follicular lymphoma (the only patient with ITP
among 81 consecutive patients with follicular lym-
phoma in our centre). ITP was diagnosed four years
prior to the diagnosis of lymphoma and responded to
prednisone with a sustained complete remission.
ITP in myeloma
The association of ITP-myeloma was reported in five
cases (three male, two females).31-32 In two cases ITP
| 448 | haematologica | 2008; 93(3)
occurred 15 months and five years prior to the diagno-
sis. All patients had IgG myeloma (three lambda, two
kappa). Four patients had a response of ITP to steroids
and/or HD-IgG, but response was usually not sus-
tained. There were no or only minor responses of ITP
after chemotherapy.31 One patient had a sustained PR
after splenectomy.32
ITP in aggressive B-cell lymphomas
In 10 cases an aggressive B-cell lymphoma was asso-
ciated with ITP. The male/female ratio was 2.3.24,33-40 In
three cases ITP occurred four, 18 and 46 months prior
to the diagnosis,24,34-35 in five cases concurrently with
lymphoma33,36,38-40 and in two after diagnosis (and che-
motherapy).35,37 Nine patients had DLCL, in one the his-
tological diagnosis was not specified.37 Six of the
patients with DLCL had a primary extranodal lym-
phoma (Stage IE or IIE) of the adrenals,33,38,40 heart,37 kid-
ney39 or mesentery.36 Only one patient (ITP before lym-
phoma) had a CR of ITP after steroids,35 all the others
had only partial or no responses. Two patients with
adrenal lymphoma40 and one with kidney lymphoma39
achieved a sustained CR after surgery/splenectomy or
chemotherapy and two37-38 achieved a PR of ITP after
chemotherapy.
ITP in T-cell lymphomas
In the literature, ITP was reported in only three cases
with T-cell lymphomas.41-43 Lymphoma diagnoses were
hepatosplenic T-cell lymphoma in two cases41-42 and
highly malignant T-cell lymphoma.43 In all cases, ITP
was diagnosed 1.5-4 months before lymphoma. Only 1
patient had a sustained CR after steroid monotherapy.43
Two patients received chemotherapy one of whom
achieved a sustained CR and the other a tCR.
In an original series of 40 patients with peripheral T-
cell lymphoma in our institute we found no case of ITP.
A renal transplant patient with severe bleeding ten-
dency due to an antibody to GP IIB/IIIA without
thrombocytopenia (acquired thrombasthenia) was
reported by Tholouli et al.44 Acquired thrombasthenia
was successfully treated with cyclophosphamide, but
the patient later developed AIHA and an angioim-
munoblastic lymphoma. A similar case of acquired
thrombasthenia was reported by Kubota et al.45 after a
malignant lymphoma of the stomach. The patient later
became thrombocytopenic along with recurrence of
lymphoma.
ITP after autologous stem cell transplantation (ASCT)
ITP occurred in eight patients after autologous stem
cell transplantation in a heterogeneous group of NHL
(two follicular lymphomas, one mantle cell lymphoma,
two DLCL, one T-cell rich B-cell lymphoma, one
Burkitt lymphoma and two highly malignant T-cell
lymphomas).46-48 The male/female ratio was 1.0 and the
median age 45 years. All underwent peripheral stem
 Autoimmune thrombocythemia in non-HL

cell transplantation, two in CR and six in PR. ITP

Table 1. Autoimmune hemolytic anemia, autoimmune thrombo-
(including one Evanss syndrome) occurred after a cythemia, and Evans syndrome in various non-Hodgkins lym-
median of five months (range 1-31 months). With one phoma-subtypes.
exception,48 all patients were in CR at onset of ITP. The
platelet counts ranged from 1,000 to 21,000/L (median Non-Hodgkins lymphoma subtype AIHA ITP Evanss syndrome
7,000/L). The megakaryocytes in the bone marrow Small lymphocytic lymphoma 0 1 0
were normal in four and decreased in two cases. Follicular lymphoma 12 1 0
Antibodies against GP IIB/IIIA were found in two Marginal cell lymphoma 14 7 0
Mantle cell lymphoma 0 1 0
patients. All except the patient with relapse responded Hairy cell lymphoma 6 2 1
to steroids and achieved a sustained CR after steroids Lymphoplasmacytic lymphoma 0 3 0
alone or after SE.46 Only one with ITP in relapse of lym- Multiple myeloma 10 5 0
High grade B-cell lymphoma 25 10 2
phoma died. T-cell lymphoma 22 3 4
References 4 1-71,87 4,72-86
AIHA: autoimmune hemolytic anemia. ITP: autoimmune thrombocythemia.
Discussion

Non-hematologic autoimmune diseases are common Table 2. Autoimmune thrombocythemia in non-Hodgkins lym-
phoma.
and often precede the diagnosis of lymphoma.1-3,14,49
Among the hematologic autoimmune disorders, AIHA
is more common than ITP while in CLL, AIHA was 3.3 Sex (M/F) 21/12
Median age (range) 53 (8-88 years)
times more common than ITP (8-11). Both are less fre- ITP prior to lymphoma 15
quent in non-CLL NHL and AIHA was only approxi- ITP at onset of lymphoma 13
mately twice as frequent as ITP (AIHA 1.57%, ITP ITP in the course of lymphoma 4
0.76%).8,12-14,17 In Hodgkins disease, AIHA and ITP were Bone marrow megakaryocytosis 20/23*
less common and equally frequent (AIHA 0.52, ITP PA-IgG increased 9/10*
P-glycoprotein antibodies 4/5*
0.79%).8,12,51,52 (Table 1)
We analyzed 33 cases of ITP and NHL reported in the *Number of positive results/patient evaluated.
literature (including one unreported case from our
department). This is about one third of the number of
reported cases of AIHA and NHL (n= 86).4 While cases Table 3. Treatment of autoimmune thrombocythemia in non-
Hodgkins lymphoma.
of AIHA and ITP were reported in a similar relative fre-
quency in MZL, HCL, myeloma and DLCL there was a
large difference in follicular lymphomas, T-cell lym- Number of CR Transient PR NR
treatments CR
phomas and lymphoplasmacytic lymphoma (Table 1).
The dominant types of lymphomas in rheumatoid Prednisone IgG 29 3 8 7 11
arthritis are DLCL and lymphoplasmacytic lym- Splenectomy 16 6 4 2 4
phoma,1,53 MZL and MALT lymphoma are more com- Surgery and/or 20 11 1 2 6
[antilymphoma
mon in Sjgrens syndrome and Hashimoto thyreoidi- [chemotherapy
tis.1,3 Patients with celiac disease have a highly Rituximab 4 2 1 1 0
increased risk of gastrointestinal and T-cell lym-
CR: complete remission. PR: partial remission. NR: no remission.
phomas.1
The prevalence of ITP in lymphoma studies was 0/92
in myeloma,8 4% in MZL (54), 1.2% in follicular lym- of patients with ITP in subtypes of NHL was too small
phomas (our department), 3.810% in makroglobuline- to evaluate prevalence according to gender. The study
mia,10,28,55 and 9% in mantle cell lymphoma.56 In T-cell has provided some data on the pathogenesis of ITP.
lymphomas a prevalence of 11.1%57 and in AILD preva- The findings of a production of a platelet antibody by
lence of 24%58,59 of thrombocytopenias was reported, an extranodal aggressive lymphoma38 and the demon-
but pathogenesis was not determined (Table 2 and 3). stration of IgM platelet antibodies in lymphoplasma-
The diagnosis of idiopathic ITP is essentially based as cytic lymphoma27 support the assumption that in some
previously described60-63 and associated with bleeding cases the platelet antibody is produced by lymphoma
symptoms.64,65 Five of the patients died, but none from tissue itself. Idiopathic ITP, ITP in CLL and ITP preced-
uncontrolled bleeding. Although cases of functional ing NHL respond well to steroids, high dose immuno-
impairment of GP IIB/IIIA by anti-GP antibodies have globulin and/or splenectomy.60,69 By contrast, ITP, which
been described in NHL,44,68 a functional abnormality has occurs at or after diagnosis of NHL, usually shows a
not been observed in patients with NHL-ITP. NHL-ITP poor response to these treatments (Table
is more frequent in males (Table 1), in contrast to 3).19,2224,26,27,29,31,33,35,38,70,71 No sustained complete remissions
female predominance in idiopathic ITP.64-67 The number after steroids alone were documented in these patients.

haematologica | 2008; 93(3) | 449 |

A.H. Hauswirth et al.

On the other hand, sustained CRs were observed after
surgical removal of the lymphoma21 or after anti-lym-
phoma chemotherapy. More than a half (64%) of the
NHL-ITP achieved a CR after anti-lymphoma treat-
ment. Interestingly, ITP in myeloma did not respond to
chemotherapy, but did respond to steroids and/or SE.
Therefore, the optimal treatment of NHL-ITP may be
different from the standard treatment. Only in SLVL
may splenectomy be the first line treatment of choice,
similar to AIHA.4
The pathogenesis and treatment of ITP following
autologous stem cell transplantation for NHL seems to
be quite different.46-48 These usually severe thrombocy-
topenias respond well to steroids and some late spon-
taneous remissions were recorded similar to idiopathic
ITP and ITP in Hodgkins disease.52 In contrast to CLL,
ITP may have been triggered by treatment only in a
few cases26,37 since the majority of ITP occurred at the
time of diagnosis of lymphoma or prior to diagnosis.
We observed one patient in our institute with a severe
ITP during a treatment with rituximab, fludarabin and
cyclophosphamide. Therefore, patients suffering from
B-CLL in association with ITP should have a personal-
ized treatment program.87 Any association of NHL and
ITP which changes the prognosis of the patients should
be studied carefully. Analysis of these cases may be
useful for physicians dealing with these patients and
may help select the best treatment option.
Authorship and Disclosures
The manuscript was read and approved by all co-
authors and all persons listed as authors made a signif-
icant contribution to its content. The authors reported
no potential conflicts of interest.

Brittinger G. Spectrum and frequen- immune disease and chronic lym-

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